Today the Duke Margolis Center and the FDA held a workshop
to discuss how to approach clinical trial designs for rare diseases. Full
disclosure – I mainly watched the summary discussion session. Much of the
earlier discussion on the details of Bayesian statistics escaped me. The rare
diseases that were the subjects of this meeting were mainly things like
muscular dystrophy and inherited metabolic diseases in children. Bacterial
infections and targeted therapies were mentioned, though. Most of the
discussion, therefore, revolved around superiority trials.
I know that some antibiotic developers have very strong
negative feelings about superiority trials.
I am not among them. I do not agree that once a drug has been shown to
be superior to a given therapy, that drug then must be used as the control in
further superiority trials. I am also not sure that non-inferiority trials are
even feasible for pathogen-specific therapies even with a wider non-inferiority
margin. As I mentioned in a previous blog,
in spite of the fact that ceftazidime-avibactam is available to treat resistant
infections, our old, inferior drugs, polymyxin and colistin are still being
used very frequently. This suggests that clinicians and pharmacists are not
convinced of ceftazidime-avibactam’s superiority to the polymyxins. (How this could be true escapes me!) Therefore they continue to use the
cheaper product.
Key concepts included the use of Bayesian designs where
non-trial data is used to established “priors.” Questions that many of us have
asked in the past revolve around exactly what kinds of data can be included
here. I would think that, for antibiotics, in vitro data, in vivo animal models
and both preclinical and clinical PK/PD could be useful in establishing priors.
Such data could even lead to modeling of response in the clinic. Could these models be used as well? Other useful
prior data might include early clinical trial data that might have been
generated before embarking on pivotal trials.
In this regard, clinical trial networks could be extremely
useful. Data that might be used in the to streamline the trial itself might
include natural history data from registries.
A clinical trial network that participates in late stage clinical trials
might also be able to provide this registry data. Such a network might also be able to utilize a
master protocol for various new antibiotics targeting smaller populations.
Data from prospective observational studies might also be
useful to help establish control levels of response and to provide a better
understanding of contemporaneous natural history of the infection of interest. Such
data could also come from the network, but does not necessarily have to be from
the network.
These concepts fit well with the latest draft of the FDA’s
unmet needs guidance. This guidance discusses the use of
superiority trials, external controls and the use of Bayesian approaches. They
even state that a statistical finding for superiority for a pathogen specific antibiotic targeting patients with unmet needs might be less stringent
than the usual standard.
An idea that has been discussed elsewhere
is pre-enrollment or early consent.
This fits well with another concept discussed in detail at today’s
conference – that of patient participation in these decisions. Pre-enrolling patients allows patients and
their families to consider a study without the urgent pressure of an ongoing
severe infection where the patient is less likely to be able to be an active
participant in the decision.
Finally, the FDA emphasized that they are open for
business. They want developers to speak
to them. I didn’t hear the antimicrobial group at the portion of the conference
I viewed, but I believe that their attitude is similar. This conference was
encouraging and makes me believe that we are slowly closing in on ways to study
and market antibiotics focused on limited patient populations.
I must also remind everyone that no matter how much we
progress on the regulatory front, unless we solve the problem of the
marketplace, we will continue to struggle to provide the robust antibiotic pipeline
that we so desperately need.
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